Siklos

Warnings and Precautions, Test Interference ( 5.8 ) 11/2023 Drug interactions, Test Interference ( 7.3 ) 11/2023

1 INDICATIONS AND USAGE SIKLOS ® is indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises SIKLOS is an antimetabolite, indicated to reduce the frequency of painful crises and to reduce the need for blood transfusions in adult and pediatric patients, 2 years of age and older, with sickle cell anemia with recurrent moderate to severe painful crises. ( 1 )

2 DOSAGE AND ADMINISTRATION Initial dose: 15 mg/kg in adults and 20 mg/kg in children once daily. Monitor blood counts every two weeks. ( 2.1 ) The dose may be increased by 5 mg/kg/day every 8 weeks, or sooner if a severe painful crisis occurs, until a maximum tolerated dose or 35 mg/kg/day is reached if blood counts are in an acceptable range. ( 2.1 ) Discontinue SIKLOS until hematologic recovery if blood counts are considered toxic. Resume treatment after reducing the dose by 5 mg/kg/day from the dose associated with hematological toxicity. ( 2.1 ) Renal impairment: Reduce the dose of SIKLOS by 50% in patients with creatinine clearance less than 60 mL/min. ( 2.2 , 8.6 , 12.3 ) 2.1 Recommended Dosing The recommended SIKLOS dosing is described in Table 1. Table 1: Dosing Recommendation Based on Blood Count Dosing Regimen Dose Dose Modification Criteria Monitoring Parameters Initial Recommended Dosing Adults: 15 mg/kg Pediatrics: 20 mg/kg once daily based on patient's actual or ideal weight, whichever is less. Monitor the patient's blood count every 2 weeks [see Warnings and Precautions (5.1) ] . Dosing Adjustment Based on Blood Counts in an acceptable range Increase dose 5 mg/kg/day every 8 weeks or if a painful crisis occurs. Give until mild myelosuppression (absolute neutrophil count 2,000/uL to 4,000/uL) is achieved, up to a maximum of 35 mg/kg/day. Increase dosing only if blood counts are in an acceptable range. Increase dosing if a painful crisis occurs. Do not increase if myelosuppression occurs. Blood Counts Acceptable Range: - neutrophils greater than or equal to 2,000 cells/mm 3 - platelets greater than or equal to 80,000/mm 3 - hemoglobin greater than 5.3 g/dL - reticulocytes greater than or equal to 80,000/mm 3 if the hemoglobin concentration less than 9 g/dL Dosing Adjustment Based on Blood Counts in a toxic range Discontinue treatment. If blood counts are considered toxic, discontinue SIKLOS until hematologic recovery. Blood Counts Toxic Range: - neutrophils less than 2,000 cells/mm 3 younger patients with lower baseline counts may safely tolerate absolute neutrophil counts down to 1,250/mm 3 . - platelets less than 80,000/mm 3 - hemoglobin less than 4.5 g/dL - reticulocytes less than 80,000/mm 3 if the hemoglobin concentration less than 9 g/dL Dosing After Hematologic Recovery Reduce dose by 5 mg/kg/day. Reduce the dose from the dose associated with hematologic toxicity. May titrate up or down every 8 weeks in 5 mg/kg/day increments. The patient should be at a stable dose with no hematologic toxicity for 24 weeks. Discontinue the treatment permanently if a patient develops hematologic toxicity twice. Siklos is available in 100 mg and 1,000 mg tablets. The 100 mg tablets have 1 score line and can be split into 2 parts (each 50 mg). The 1,000 mg tablets have 3 score lines and can be split into 4 parts (each 250 mg). Therefore, the two strengths can be used to deliver doses of 1,000 mg, 750 mg, 500 mg, 250 mg, 100 mg, 50 mg and combinations thereof. Calculate the rounded doses to the nearest 50 mg or 100 mg strength based on clinical judgment. Patients must be able to follow directions regarding drug administration and their monitoring and care. Fetal hemoglobin (HbF) levels may be used to evaluate the efficacy of SIKLOS in clinical use. Obtain HbF levels every three to four months. Monitor for an increase in HbF of at least two-fold over the baseline value. Administration: The tablets should be taken once daily, at the same time each day, with a glass of water. For patients who are not able to swallow the tablets, these can be dispersed immediately before use in a small quantity of water in a teaspoon. SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15) ]. 2.2 Dose Modifications for Renal Impairment Reduce the dose of SIKLOS by 50% in patients with creatinine clearance of less than 60 mL/min or with end-stage renal disease (ESRD) [see Use in Specific Populatio …

3 DOSAGE FORMS AND STRENGTHS Tablets: functionally scored 100 mg and functionally triple-scored 1,000 mg tablet ( 3 ) Tablets: 100 mg tablets: off-white, capsule-shaped, film-coated, functionally scored tablet with scoring on both sides which can be divided into two equal parts, each part is debossed with "H" on one side. 1,000 mg tablets: off-white, capsule-shaped, film-coated, functionally triple-scored tablet with scoring on both sides which can be divided into four equal parts, each part is debossed with "T" on one side.

4 CONTRAINDICATIONS SIKLOS is contraindicated in: Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation [see Adverse Reactions (6) ]. Patients who have demonstrated a previous hypersensitivity to hydroxyurea or any other component of its formulation. ( 4 )

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelosuppression [see Warnings and Precautions (5.1) ] Malignancies [see Warnings and Precautions (5.2) ] Vasculitic toxicities (including Leg Ulcers) [see Warnings and Precautions (5.4) ] Risks with concomitant use of antiretroviral drugs [see Warnings and Precautions (5.5) ] Risk with concomitant use of live virus vaccine [see Warnings and Precautions (5.6) ] Macrocytosis [see Warnings and Precautions (5.7) ] Hemolytic Anemia [see Warnings and Precautions (5.9) ] Most common adverse reactions to SIKLOS (incidence > 10%) include infections and neutropenia in children and infections and headache and dry skin in adults. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact the marketer Medunik at 1 844-884-5520 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of SIKLOS has been assessed in 405 pediatric patients with sickle cell disease from 2-18 years of age and 1077 adults in the European Sickle Cell Disease prospective Cohort study ESCORT-HU. The most frequently reported adverse reactions in ESCORT-HU were infections and myelosuppression, with mild to moderate neutropenia as the most common manifestation. Other adverse reactions include skin and subcutaneous disorders (skin depigmentation/melanonychia, skin rash, alopecia), gastrointestinal disorders, vitamin D deficiency and headache. At least one serious adverse reaction was reported in 33% of the 405 pediatric patients and 32% of the 1077 adults with sickle cell disease in ESCORT-HU. The most frequent serious adverse reactions were infections (18%), and blood and lymphatic system disorders (9%) in children, including serious neutropenia (3.2%), thrombocytopenia (3%) and anemia (3%). Other reported serious adverse reactions were gastrointestinal disorders (3.2 %), fever (2.5 %) and nervous system disorders (4%), including headache (2.7%). Among adults, the most frequent serious adverse reactions were infections (12.9%), respiratory, thoracic and mediastinal disorders (5.8%), blood and lymphatic disorders (4.8%), nervous system disorders (3.6%), and general disorders and administration site disorders (3.1%). Table 2: Most frequent (greater than or equal to 2%) adverse reactions reported in pediatric patients enrolled in ESCORT-HU Global Safety Set (N=405) Total Severity Mild Moderate Severe n % n % n % n % n: number of patients with an adverse reaction At least one adverse reaction 261 64 Infections 161 40 120 30 88 22 18 4.4 Other Infections 92 23 66 16 32 8 3 0.7 Bacterial 65 16 24 6 37 9 10 2.5 Viral 40 10 23 6 14 3.5 3 0.7 Parvovirus B19 15 4 7 1.7 5 1.2 2 0.5 Blood and lymphatic system disorders 85 21 51 13 59 15 14 3.5 Neutropenia 51 13 26 6 31 8 4 1 Thrombocytopenia 30 7 16 4 15 3.7 2 0.5 Anemia 17 4.2 4 1 8 2 7 1.7 Gastrointestinal disorders 53 13 29 7 30 7 4 1 Other Gastrointestinal Disorders 30 7 13 3.2 15 3.7 2 0.5 Constipation 10 2.5 5 1.2 5 1.2 0 0 Nausea 10 2.5 4 1 4 1 2 0.5 Metabolic and nutrition disorders 44 11 24 6 21 5 1 0.2 Deficiency of vitamin D 25 6 19 4.7 7 1.7 1 0.2 Other Metabolic and nutrition disorders 8 2 3 0.7 4 1 1 0.2 Weight gain 8 2 1 0.2 7 1.7 0 0 Nervous system disorders 45 11 19 4.7 19 4.7 8 2 Headache 30 7 15 3.7 7 1.7 4 1 Other Nervous system disorders 11 2.7 2 0.5 4 1 4 1 General disorders 41 10 22 5 17 4.2 4 1 Fever 31 8 20 4.9 12 3 2 0.5 Skin and subcutaneous tissue disorders 38 9 29 7 14 3.5 1 0.2 Skin reactions 15 4 8 2 7 1.7 1 0.2 Other Skin and subcutaneous tissue disorders 13 3.2 8 2 5 1.2 0 0 Other Not SCD-related reactions 23 6 16 4 3 0.7 1 0.2 Other Not SCD-related reactions 23 6 16 4 3 0.7 1 0.2 Respiratory tho …

7 DRUG INTERACTIONS 7.1 Increased Toxicity with Concomitant Use of Antiretroviral Drugs Pancreatitis Pancreatitis (including fatal cases) have occurred in patients with HIV infection during therapy with hydroxyurea and didanosine, with or without stavudine. Hydroxyurea is not indicated for the treatment of HIV infection; however, if patients with HIV infection are treated with hydroxyurea, and in particular, in combination with didanosine and/or stavudine, monitor closely for signs and symptoms of pancreatitis. Permanently discontinue therapy with hydroxyurea in patients who develop signs and symptoms of pancreatitis. Hepatotoxicity Hepatotoxicity and hepatic failure resulting in death have been reported during postmarketing surveillance in patients with HIV infection treated with hydroxyurea and other antiretroviral drugs. Fatal hepatic events were reported most often in patients treated with the combination of hydroxyurea, didanosine, and stavudine. Avoid this combination. Peripheral Neuropathy Peripheral neuropathy, which was severe in some cases, has been reported in patients with HIV infection receiving hydroxyurea in combination with antiretroviral drugs, including didanosine, with or without stavudine. 7.2 Concomitant Use of Live Virus Vaccine Concomitant use of SIKLOS with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reactions of the vaccine virus, because normal defense mechanisms may be suppressed by SIKLOS therapy. Vaccination with a live vaccine in a patient taking SIKLOS may result in severe infections. Generally, the patient's antibody response to vaccines may be decreased. Treatment with SIKLOS and concomitant immunization with live virus vaccines should only be performed if benefits clearly outweigh potential risks. Consider consultation with a specialist. 7.3 Test Interference Interference with Uric Acid, Urea, or Lactic Acid Assays Studies have shown that there is an analytical interference of SIKLOS with the enzymes (urease, uricase, and lactate dehydrogenase) used in the determination of urea, uric acid, and lactic acid, rendering falsely elevated results of these in patients treated with SIKLOS. Interference with Continuous Glucose Monitoring Systems Hydroxyurea may falsely elevate sensor glucose results from certain continuous glucose monitoring (CGM) systems and may lead to hypoglycemia if sensor glucose results are relied upon to dose insulin. If a patient using a CGM is to be prescribed hydroxyurea, consult with the CGM prescriber about alternative glucose monitoring methods.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise women to stop breastfeeding while taking SIKLOS. ( 8.2 ) 8.1 Pregnancy Risk Summary SIKLOS can cause fetal harm based on findings from animal studies and the drug's mechanism of action [see Clinical Pharmacology (12.1) ] . There are no studies with the use of SIKLOS in pregnant women, and limited available data on SIKLOS use during pregnancy are insufficient to inform drug-associated risks. Drugs which affect DNA synthesis, such as hydroxyurea, may be potential mutagenic agents. In animal reproduction studies, administration of hydroxyurea to pregnant rats and rabbits during organogenesis produced embryotoxic and teratogenic effects at doses 0.8 times and 0.3 times, respectively, the maximum recommended human daily dose on a mg/m 2 basis. In rats and rabbits, fetal malformations were observed with partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, and missing lumbar vertebrae. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays (see Data ) . Advise pregnant women of the potential risk to a fetus (see Clinical Considerations ). Background risk of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. Clinical Considerations Fetal/Neonatal adverse reactions Although the data on a limited number of exposed pregnancies indicate no adverse effects on pregnancy or on the health of the fetus/newborn, patients on SIKLOS should be made aware of the potential risks to the fetus. Based on the limited amount of available information, in case of an exposure to SIKLOS of pregnant female patients or pregnant partners of male patients, treated by SIKLOS, a careful follow-up with adequate clinical, biological and ultrasonographic examinations should be considered. Data Human Data According to a retrospective analysis of a cohort of 123 adult patients treated with hydroxyurea, twenty-three pregnancies have been reported from 15 women treated with hydroxyurea and partners of 3 men not using barrier contraception treated with hydroxyurea. Most (61%) had no adverse developmental outcomes. In the other cases with known evolution, pregnancy had been interrupted either voluntarily or upon medical advice. In retrospective cohorts of 352 children and adolescents with sickle cell disease older than 2 years treated with hydroxyurea for a period of up to 12 years, 3 pregnancies under hydroxyurea were reported with no adverse developmental outcomes. From post-marketing data of SIKLOS, 3 pregnancies have been reported while the father was treated with SIKLOS and 16 pregnancies have been reported in 15 females treated with SIKLOS. Among the 13 cases with known evolution, 5 pregnancies had no adverse developmental outcomes, 4 led to premature birth, and 4 were early terminated. Animal Data Hydroxyurea has been demonstrated to be a potent teratogen in a wide variety of animal models, including mice, hamsters, cats, miniature swine, dogs, and monkeys at doses within 1-fold of the human dose given on a mg/m 2 basis. Hydroxyurea is embryotoxic and causes fetal malformations (partially ossified cranial bones, absence of eye sockets, hydrocephaly, bipartite sternebrae, missing lumbar vertebrae) at 180 mg/kg/day (about 0.8 times the maximum recommended human daily dose on a mg/m 2 basis) in rats and at 30 mg/kg/day (about 0.3 times the maximum recommended human daily dose on a mg/m 2 basis) in rabbits. Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. Hydroxyurea crosses the placenta. Single doses of ≥375 mg/kg (about 1.7 times the maximum recommended human daily dose o …

12.1 Mechanism of Action The precise mechanism by which hydroxyurea produces its cytotoxic and cytoreductive effects is not known. However, various studies support the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. The mechanisms by which SIKLOS produces its beneficial effects in patients with sickle cell Anemia (SCA) are uncertain. Known pharmacologic effects of SIKLOS that may contribute to its beneficial effects include increasing hemoglobin F levels in red blood cells (RBCs), decreasing neutrophils, increasing the water content of RBCs, increasing deformability of sickled cells, and altering the adhesion of RBCs to endothelium.

11 DESCRIPTION SIKLOS (hydroxyurea) is an antimetabolite that is available for oral use as functionally scored 100 mg film-coated tablet and functionally triple-scored 1,000 mg film-coated tablet containing 100 and 1,000 mg of hydroxyurea, respectively. Inactive ingredients include silicified microcrystalline cellulose, sodium stearyl fumarate, and film-coating agent amino methacrylate copolymer. Hydroxyurea is a white crystalline powder. It has a molecular weight of 76.05. Its structural formula is: Chemical Structure

10 OVERDOSAGE Acute mucocutaneous toxicity has been reported in patients receiving hydroxyurea at doses several times above the therapeutic dose. Soreness, violet erythema, oedema on palms and soles followed by scaling of hand and feet, severe generalized hyperpigmentation of the skin and stomatitis have been observed. In patients with sickle cell anemia, neutropenia was reported in isolated cases of hydroxyurea overdose (1.43 times and 8.57 times of the maximum recommended dose of 35 mg/kg b.w./day). Monitor blood counts weekly until recovery. Treatment of overdose consists of gastric lavage, followed by symptomatic treatment and control of bone marrow function.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied SIKLOS (hydroxyurea) film-coated tablet is supplied in high density polyethylene (HDPE) bottle with polypropylene child-resistant cap with a desiccant unit containing 30 (SIKLOS 1,000 mg) or 60 (SIKLOS 100 mg) film coated tablets. Each bottle containing SIKLOS 100 mg tablets or SIKLOS 1000 mg tablets is supplied in a carton. SIKLOS is supplied in the following strengths: 100 mg off-white, capsule-shaped, film-coated, functionally scored tablet with scoring on both sides which can be divided into two equal parts, each part is debossed with "H" on one side. 1,000 mg off-white, capsule-shaped, film-coated, functionally triple-scored tablet with scoring on both sides which can be divided into four equal parts, each part is debossed with "T" on one side. Bottles of 30 Bottles of 60 100 mg N/A NDC 71770-105-60 1,000 mg NDC 71770-120-30 N/A 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep tightly closed. Broken tablets must be stored in the bottle and must be used within three months. 16.3 Handling and Disposal SIKLOS is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15) ] . To decrease the risk of contact, advise caregivers to wear disposable gloves when handling SIKLOS or bottles containing SIKLOS. Wash hands with soap and water before and after contact with the bottle or tablets when handling SIKLOS. Avoid exposure to crushed tablets. If contact with crushed tablets occurs on the skin, wash affected area immediately and thoroughly with soap and water. If contact with crushed tablets occurs on the eye(s), the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. Powder spilled from the broken tablet should be wiped up with a damp disposable towel which must be thrown away in a closed container such as a plastic bag to avoid ingestion of powder by other people. The spill areas should then be cleaned using a detergent solution followed by clean water.